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EP1372634A2 - Amides de l'acide fumarique - Google Patents

Amides de l'acide fumarique

Info

Publication number
EP1372634A2
EP1372634A2 EP02729423A EP02729423A EP1372634A2 EP 1372634 A2 EP1372634 A2 EP 1372634A2 EP 02729423 A EP02729423 A EP 02729423A EP 02729423 A EP02729423 A EP 02729423A EP 1372634 A2 EP1372634 A2 EP 1372634A2
Authority
EP
European Patent Office
Prior art keywords
residue
fumaric acid
amino acid
peptide
medicament
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP02729423A
Other languages
German (de)
English (en)
Other versions
EP1372634B1 (fr
Inventor
Rajendra Kumar Joshi
Hans-Peter Strebel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen International GmbH
Original Assignee
Fumapharm AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10101307A external-priority patent/DE10101307A1/de
Application filed by Fumapharm AG filed Critical Fumapharm AG
Publication of EP1372634A2 publication Critical patent/EP1372634A2/fr
Application granted granted Critical
Publication of EP1372634B1 publication Critical patent/EP1372634B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
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    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to certain fumaric acid mono- and diamonds or mono-amidofumaric acid monoesters and the use of these compounds for the manufacture of a medicament and medicaments containing these compounds.
  • Fumaric acid dialkyl esters as well as fumaric acid monoalkyl esters and salts thereof have long been used successfully for the treatment of psoriasis. This use has been described in a number of patents, see for example EP-A-0 188 749, DE-25 30 372, DE 26 21 214 or EP-B-0 312 697.
  • fumaric acid monoesters or diesters for the treatment of autoimmune disorders such as polyarthritis, multiple sclerosis (see DE 197 21 099.6 and DE 198 53 487.6) is also described, but also for use in transplantation medicine (see DE 198 53 487.6 and DE 198 39 566.3).
  • the use of fumaric acid monoesters and diesters for the treatment of NFkappaB-mediated diseases, such as the treatment of mitochondrial diseases is also known from the previously unpublished German applications DE 101 01 307.8 and DE 100 00 577.2.
  • all the cited documents only describe fumaric acid monoesters and diesters, optionally in the form of certain salts, that is to say compounds in which one or both acid functions of fumaric acid are esterified with an alcohol.
  • the fumaric acid esters mentioned have the disadvantage that they are difficult to handle in the manufacture of pharmaceutical products, in particular in solid form for oral administration. More accurate The manufacture of these products requires protective measures such as the use of breath masks, gloves, protective suits, etc.
  • the fumaric acid esters are absorbed in the gastrointestinal tract after oral administration and are absorbed unspecifically from the blood stream by all body cells.
  • high doses In order nevertheless to provide a therapeutically effective level of the active substance on or in the target cells, correspondingly high doses must be administered.
  • These high doses in turn lead to the well-known side effects of fumaric acid therapy such as flush symptoms (redness) or gastrointestinal irritation (nausea, diarrhea, flatulence).
  • the side effects can be considerably reduced by administering the active ingredient in the form of microtablets, but they cannot be completely avoided.
  • the fumaric acid esters in the blood are rapidly hydrolyzed and the hydrolysis products alcohol and fumaric acid or fumaric acid monoester are metabolized. Repeated, frequent administration is therefore required to maintain therapeutically effective levels. Although a certain habituation effect can be observed with regard to the side effects, a further reduction in the side effect rate would be desirable.
  • the present object is achieved by certain fumaric acid mono- and diamonds or monoamidofumaric acid monoesters, their use in the manufacture of medicaments for the therapy of certain diseases and medicaments containing them.
  • Fumaric acid diamides or monoamides have already been described in US Pat. No. 5,242,905 and US Pat. No. 5,214,196 to Blank for the therapy of psoriasis.
  • the cited documents only describe the production of individual fumaric acid mono- or diamides.
  • the production of pharmaceutical products and the application of the amides are not described on people.
  • the publications cite the provision of certain amino acids from the fumaramides in the keratinocytes as a theoretical advantage of the fumaramides over the fumaric acid esters in order to complete a deficient metabolism in psoriasis.
  • the present invention therefore relates to the use of fumaric acid amides of the general formula (I)
  • Ri represents OR3 or a D- or L-amino acid residue -NH-CHR4-COOH bonded via an amide bond, wherein R3 is hydrogen, a straight-chain or branched, optionally substituted C ⁇ -24-alkyl residue, preferably C ⁇ -6-alkyl residues, a phenyl residue or C ⁇ -io-aralkyl radical and R4 is a side chain of a natural or synthetic amino acid, and
  • R2 stands for a D- or L-amino acid residue -NH-CHR5-COOH bound via an amide bond or a peptide residue with 2 to 100, preferably 2 to 30 amino acids bound via an amide bond, wherein R5 is a side chain of a natural or synthetic amino acid Manufacture of a drug
  • mitochondrial diseases selected from the group consisting of Parkinson's syndrome, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa or mitochondrial encephalomyopathies and
  • NFkappaB-mediated disorders selected from the group consisting of progressive systemic skis or mie, osteochondritis syphilitica (Wegener's Disease), cutis marmorata, (Livedo Reticularis), Behcet disease, panarteritis, ulcerative colitis, Vasculitis, osteoarthritis, gout, aterioslderosis, Reiter's disease, bronchocentic granulomatosis, encephalitis types, endotoxin shock (septic-toxic shock), sepsis, pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (the - kuten hepatitis, chronic hepatitis, toxic hepatitis, alcohol hepatitis, viral hepatitis, jaundice, hepatic insufficiency and cytomegaloviral hepatitis), Rennert T lymphomatosis, mesangial
  • ralgia postherpetic neuralgia
  • inflammatory demyelinating polyneuropathy mononeuropathia multiplex
  • cystic fibrosis ankylosing spondylitis
  • beret esophagus EBV (Epstein-Barr virus) infection
  • cardiac remodeling English: cardiac remodeli
  • interstitial cystitis type ⁇ diabetes
  • the radiation sensitization of malignant tumors English: human tumor radiosensitization
  • the multiple resistance of malignant cells to chemotherapeutic agents English: multidrug resistance in chemotherapy
  • granuloma annular and cancers such as breast cancer, colon cancer, Melanoma, primary liver cell carcinoma, adenocarcinoma, Kaposi's sarcoma, prostate carcinoma
  • leukemia such as acute yeloid see leukemia, multiple myeloma (plasmacytoma), Burkitt's lymphoma, and the Castleman tumor.
  • the present invention relates to fumaric acid amides of the formula (I)
  • Ri represents OR3 or a D- or L-amino acid residue -NH-CHR4-COOH bonded via an amide bond, in which R_ ⁇ is hydrogen, a straight-chain or branched, optionally substituted C ⁇ -24-alkyl residue, preferably C ⁇ -6-alkyl residue, is a phenyl radical or co-io-aralkyl radical and R 4 is a side chain of a natural or synthetic amino acid, and
  • side chain of a natural or synthetic amino acid means the residues of any natural or synthetically produced amino acid which are at the ⁇ -carbon atom of the amino acid.
  • the amino acid residues Ri and R2 can be in the D and L configurations. The natural L configuration is preferred. In the following, the usual abbreviations or designations in the three-letter code are used to identify the amino acids.
  • Ri represents an L-amino acid residue -NH-CHR.-COOH
  • R_ represents an L-amino acid residue -NH-CHR5-COOH
  • Ri and R > may be the same or different and have the meaning given above.
  • R4 and R5 are more preferably selected independently of one another from the group consisting of the side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrulline, Hey, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.
  • compounds of the formula (I) are used or claimed in which Ri is -01k and R2 is an L-amino acid residue -NH-CHR _> - COOH, in which R. is selected from the group consisting of Side chains from Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hey, Hse, Hyp, Hyl, Orn, Sar, and Me -Gly.
  • Rs is very particularly preferably a polar amino acid, even more preferably a charge-carrying amino acid, selected from the group consisting of asparagine, glutamine, lysine, arginine and histidine.
  • R 1 is -OR 3, ie the compound of the formula (I) to be used or claimed according to the invention is a monoamido-fumaric acid monoester or a mono-id, R.
  • a linear, branched, cyclic, saturated or unsaturated C ⁇ -24-alkyl radical preferably a C ⁇ -6-alkyl radical, phenyl or a Cö-io-aralkyl radical, and this radical is optionally halogen (F, Cl, Br, I), hydroxy, Cwalkoxy, nitro or cyano substituted.
  • R3 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy - ethyl, 2-or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxymethyl or 2- or 3-methoxypropyl. Most preferred is R. methyl or ethyl.
  • the peptide residue can be a natural, a recombinant or synthetic peptide residue.
  • the peptide residue Rz is more preferably selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, antibody fragments, coagulation factors and cyclosporins as well as derivatives and fragments thereof.
  • the peptides can be purified from natural sources, obtained recombinantly or synthesized according to known methods. Synthetic peptides are preferably used.
  • the coupling of the fumaric acid body to such a functional peptide has the advantage that the peptide can be used to transmit the active substance “fumaric acid body” to target cells with which the peptide portion of the amides according to the invention interacts.
  • the peptide portion can have its own effect on the disease to be treated, so that in this case a combination therapy can be effected.
  • Combination therapy and / or targeted administration allow reducing the dose to be administered in a desirable, possibly even synergistic manner.
  • the peptide residue can be a cyclosporin residue, the cycle of which can be cleaved at each peptide bond in order to enter into the fumaric acid amide bond.
  • all cyclosporins can in principle be bound to the fumaric acid body via an amide bond. Since cyclosporins are cyclic peptides, the peptide ring of the cyclosporin is basically cleaved at any point (at any amide bond) in order to obtain a linearized cyclosporin which is capable of forming an amide bond. Cyclosporin A linearized before position 1 is preferred.
  • peptide hormones as used here means physiologically highly active peptides which develop hormone or hormone-like effects, with approximately up to 100 amino acids.
  • examples include the glandular peptide hormones of the pituitary gland, such as corticotropin, follitropin, lutropin, melanotropin, prolactin, somatotropin, thyrotropin, oxytocin and vasopressin, releasing hormones and inhibiting factors Hypothalamus, the peptide hormones from pancreas, stomach or intestine such as glucagon, insulin, somatostatin, spectrin, gastrin and cholecystokinin, peptide hormones of the thyroid such as calcitonin and parathyrin and the like.
  • growth factors refers to hormone-like peptides and proteins that promote cell division and differentiation, ensure growth and organ development, and are used for wound healing. Examples of these are colony-stimulating factors, the epidermal growth factor (EGF), erythropoietin, fibroblast growth factors, hematopoietic growth factors, hepatocyte growth factors, insulin and insulin-like growth factors, the plathelet derived growth factor (PDGF), thrombopoietin, transforming growth factors , viral growth factors, but also the interleukins.
  • cytokines as used here means polypeptides which are secreted by cells and which, after binding to specific receptors, can influence the function of other, usually neighboring cells. Above all, cytokines regulate the complicated interplay of the cells of the immune system. Examples of such cytokines are interferons, interleukins, chemokines or colony-stimulating factors.
  • neurotransmitter means messenger substances that cause the signal or information to be transmitted chemically at the synapses of the nervous system.
  • amino acids such as glutamic acid, amino acid derivatives such as acetylcholine, monoamines such as catecholamines such as L-noradrenaline, L-adrenaline and dopamine, serotonin and peptides according to their chemical nature.
  • monoamines such as catecholamines such as L-noradrenaline, L-adrenaline and dopamine
  • serotonin and peptides according to their chemical nature.
  • a subset of the neurotransmitters are accordingly the “neuropeptides” such as bradykinin, but also the enkephalins, the endorphin, etc.
  • coagulation factors means proteins of the coagulation cascade.
  • the peptide to be coupled according to the invention via an amide bond to the fumaric acid can be an antibody fragment, this fragment preferably also comprising a recognition sequence and / or a binding sequence.
  • Fragments and / or derivatives thereof can also be used from all the peptides mentioned which are suitable according to the invention.
  • fragment means a portion of the above-mentioned peptides capable of amide binding.
  • the section preferably comprises recognition sequences for the mediation of a binding to a cell receptor and / or an active center for the transmission of an active function.
  • the term "derivative" means a peptide which can be derived from the above-mentioned peptides and / or fragments by homologous substitution, deletion or insertion of one or more amino acids into or from the peptide chain.
  • the fumaric acid amides of the invention can be made according to Blank's US patents noted above.
  • the present invention relates to medicaments containing a fumaric acid amide as defined above or mixtures thereof.
  • the medicaments obtained via the use according to the invention and / or through the use of the claimed fumaric acid amides can be in a form suitable for oral, nasal, parenteral, rectal, pulmonary, ophthalmic or transdermal administration.
  • the medicament is preferably intended for oral administration and is in the form of tablets, dragées, capsules, granules, drinking solutions, liposomes, nanocapsules, microcapsules, microtablets, pellets or powders and granules filled in capsules, microtablets filled in capsules, capsules filled in capsules Pellets or powder filled in capsules.
  • the medicament is a solid oral dosage form and then even more preferably has an enteric coating.
  • this coating can be provided on tablets, dragées, microtablets, pellets or capsules.
  • the medicament according to the invention can contain suitable, pharmaceutically acceptable carriers, auxiliaries, additives, etc. These are known to the person skilled in the art and do not require any explanation.
  • microtablets or pellets preferably have an average diameter of 300 to 5000 ⁇ m without coating, more preferably 300 to 2000 ⁇ m.
  • the preparation is in a suitable form. All common liquid carriers suitable for injection can be used.
  • the medicament contains an amount of the fumaric acid amide of the formula (I) per single dose which corresponds to an amount of 1 to 500 mg, preferably 10 to 300 mg and most preferably 10 to 200 mg of fumaric acid or is equivalent.

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Abstract

L'invention concerne des amides de l'acide fumarique, de formule générale (I), dans laquelle R1 représente OR3 ou un groupe acide aminé D ou L -NH-CHR4-COOH lié par une liaison amide, R3 représentant un atome d'hydrogène, un groupe alkyle C1-24 linéaire ou ramifié, éventuellement substitué, un groupe phényle ou un groupe aralkyle C6-10 et R4 représentant une chaîne latérale d'un acide aminé naturel ou synthétique, et R2 représente un groupe acide aminé D ou L -NH-CHR5-COOH lié par une liaison amide ou un groupe peptide lié par une liaison amide et comprenant 2 à 100 acides aminés, R5 représentant une chaîne latérale d'un acide aminé naturel ou synthétique. Selon l'invention, ces amides de l'acide fumarique sont utilisés pour produire un médicament utilisé (1) pour traiter une maladie auto-immune, (2) en médecine de transplantation, (3) pour traiter des maladies mitochondriales et (4) pour traiter des maladies médiées par NfkappaB.
EP02729423A 2001-01-12 2002-01-08 Utilisation d'amides de l'acide fumarique Expired - Lifetime EP1372634B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10101307 2001-01-12
DE10101307A DE10101307A1 (de) 2001-01-12 2001-01-12 Fumarsäurederivate als NF-kappaB-Inhibitor
DE10133004 2001-07-06
DE10133004 2001-07-06
PCT/EP2002/000107 WO2002055063A2 (fr) 2001-01-12 2002-01-08 Amides de l'acide fumarique

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EP1372634A2 true EP1372634A2 (fr) 2004-01-02
EP1372634B1 EP1372634B1 (fr) 2009-11-11

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US (2) US7157423B2 (fr)
EP (1) EP1372634B1 (fr)
JP (1) JP2004523511A (fr)
AT (1) ATE447945T1 (fr)
AU (1) AU2002219236B2 (fr)
BG (1) BG66256B1 (fr)
CA (2) CA2425599C (fr)
CZ (1) CZ304198B6 (fr)
DE (1) DE50213989D1 (fr)
EE (1) EE05472B1 (fr)
HU (1) HU230252B1 (fr)
ME (1) ME00135B (fr)
NO (1) NO333992B1 (fr)
NZ (1) NZ526100A (fr)
PL (3) PL392750A1 (fr)
RS (1) RS52083B (fr)
RU (1) RU2290946C2 (fr)
SK (1) SK288238B6 (fr)
WO (1) WO2002055063A2 (fr)

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US20040038889A1 (en) 2004-02-26
CA2776023A1 (fr) 2002-07-18
WO2002055063A2 (fr) 2002-07-18
US7432240B2 (en) 2008-10-07
CZ304198B6 (cs) 2013-12-27
HUP0302656A2 (hu) 2003-11-28
ATE447945T1 (de) 2009-11-15
EE200300280A (et) 2003-10-15
AU2002219236B2 (en) 2006-02-09
CA2425599C (fr) 2012-04-24
EP1372634B1 (fr) 2009-11-11
ME00135B (fr) 2012-06-03
JP2004523511A (ja) 2004-08-05
PL392750A1 (pl) 2011-05-23
RS52083B (sr) 2012-06-30
SK288238B6 (sk) 2015-01-07
EE05472B1 (et) 2011-10-17
DE50213989D1 (de) 2009-12-24
CZ20031919A3 (en) 2004-04-14
PL392748A1 (pl) 2011-05-09
RS56003A (sr) 2006-12-15
WO2002055063A3 (fr) 2003-10-09
HU230252B1 (hu) 2015-11-30
NO333992B1 (no) 2013-11-11
RU2290946C2 (ru) 2007-01-10
BG107795A (bg) 2004-08-31
BG66256B1 (bg) 2012-10-31
CA2425599A1 (fr) 2003-04-10
NO20031748D0 (no) 2003-04-15
HUP0302656A3 (en) 2009-08-28
US7157423B2 (en) 2007-01-02
PL364222A1 (en) 2004-12-13
RU2003124752A (ru) 2005-01-10
NZ526100A (en) 2005-04-29
SK8272003A3 (en) 2004-07-07
NO20031748L (no) 2003-09-12
US20060205659A1 (en) 2006-09-14

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